(Fast-Track) Insulin remains the primary, and often the only, treatment for type 1 diabetes mellitus (T1D). However it is associated with chronic iatrogenic hyperinsulinemia, secondary hyperlipidemia, higher incidence and severity of cardiovascular complications, and life-threatening hypoglycemia events. A higher mortality (2.7%,vs. 0.9%) due to cardiovascular complications were reported in insulin-treated T1D patients, versus the general public [3]. An effective add-on therapy is needed to reduce daily insulin doses and to minimize its complications. REMD-477 is a fully human, high affinity, glucagon receptor (GCGR) antibody, that blocks the hepatic GCGR and reduces hepatic glucose/ketone production. REMD-477 restores euglycemia in animal models of type 2 diabetes mellitus (T2D), and shows preliminary but promising glucose-lowering effect in a few T1D mouse models. REMD-477 demonstrated a benign safety profile in animals, and in healthy volunteers in a first-in- human study. Since the overactive glucagon action is a common finding in both T1D and T2D, a robust GCGR blocker, such as REMD-477, represents a promising novel strategy. In Phase I of this project, the glucose-lowering effects of REMD-477 will be thoroughly evaluated in 2 animal models of T1D, including a chemical (streptozotocin)-induced model in rats; and an autoimmune, non-obese diabetic (NOD) model in mice, both without insulin treatment. The animal studies will be directed by Dr. Roger Unger, at the Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX. In Phase II, a randomized, double-blind, vehicle-controlled, 4-day, in-patient, clinical study will be conducted i 20 patients with T1D, to quantitatively assess the reduction in insulin requirements while maintaining standardized postprandial and postabsorptive glycemic control. The study will be directed by Dr. Sam Klein, Chief, Div. of Geriatrics & Nutritional Sciences, at the Washing University School of Medicine, St. Louis, MO. The small business, REMD Inc., provides research materials, performs the hormone and metabolite assays, and coordinates the overall project management and supportive duties, for both Phase I and II of this project. REMD-477 is projected to be an add-on therapy for T1DM, to substantially (>50%) reduce insulin daily doses, leading to better glucose control, fewer and milder complications, and an improved quality of life.